Page 134 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

124 ELECTROLYTE DISORDERS

Although regulations at each parathyroid cell may fail,
thus producing abnormally increased PTH, 214,460
changes may also be seen in the maximal secretory capac-
ity dependent mostly on parathyroid cell numbers. 506 It is
likely that increased PTH secretion in patients with renal
Serum PTH 'Set point' secondary hyperparathyroidism is primarily caused by
157
One important role
parathyroid gland hyperplasia.
of calcitriol therapy in these patients is to prevent or
reverse the parathyroid cellular hyperplasia. 100,156,403
Inhibition of PTH Synthesis and Secretion
This topic has become important with the understanding
of the toxicity of PTH in animals and humans with
Serum Ca 2+
Figure 6-5 Relationship between secretion rate of parathyroid chronic renal failure (CRF) and accompanying secondary
hormone and plasma calcium concentration. Small changes in hyperparathyroidism. 11,357,401,438 Recently, increased
plasma calcium concentration cause large changes in parathyroid awareness of PTH toxicity stems from established
hormone secretion, but secretion is not completely suppressed by relations to cardiovascular disease 135 and mortality. 546
high plasma calcium concentrations. PTH secretion is inhibited by increased serum iCa con-
centration, 535,537 and the initial effect to decrease PTH
secretion is rapid (occurring within 2 to 3 minutes),
mediated by the calcium receptor with a cascade of
secretion for relatively small changes in iCa concentration resulting intracellular events 67,137,251 and involving
8
in the physiologic range and precise control of serum iCa mediation by arachidonate. Slower effects are caused
concentration. An approximate 10% decrease in serum by inhibition of synthesis of PTH mRNA and its transla-
iCa concentration elicits a nearly maximal PTH secretory tion to hormone (Fig. 6-6). 535
response. The rate of decrease of serum iCa concentration The osteocyte-derived phosphatonin 43 fibroblast
is also important, and rapid decreases in serum iCa result growth factor-23 (FGF-23) is both protectively
in larger increases in PTH secretion. A 2% to 3% decrease phosphaturic 229 and inhibitory of PTH secretion. 203
in iCa concentration, if rapid in onset, may result in a FGF-23 is induced by calcitriol 304 and in a feedback loop,
81 229
400% increase in PTH secretion. FGF-23 inhibits calcitriol synthesis. The calcimimetic
The cell membrane calcium receptor is responsible for cinacalcet (Sensipar), previously used as an alternative
establishing the relationship of the set-point for PTH to calcitriol’s PTH suppression 13 during kidney
secretion and extracellular iCa concentration. 598 The cal- disease, 543,630 has recently been shown to be
cium receptor regulates PTH secretion indirectly by contraindicated 131 due primarily to hyperphosphatemic
controlling the intracellular iCa concentration by means consequences. 284 High phosphorus is increasingly
of (1) release of iCa from intracellular stores, and (2) cell recognized 193,291,359 as the major driver of cardiovascular
membrane calcium channels. Calcium channels span the calcification, 280,367 which is the major cause of mortality
parathyroid chief cell membrane and are important in in human patients with chronic renal disease. 387
allowing extracellular iCa access to the interior of the Calcitriol, in part due to its induction of FGF-23 304 with
cell. 186 The calcium channels are controlled by intracellu- its phosphaturic effects, 229 can protect against vascular
lar iCa concentration 82 and membrane regulatory G calcification, 358,603,627 which is likely instrumental in
proteins, which interact with the cell membrane calcium the now widely recognized improved survival associated
receptor. 24 with use of calcitriol 621 and other active vitamin D
Calcitriol plays an important role in controlling the metabolites. 620 Cinacalcet, although it suppresses
parathyroid gland set-point by regulating (1) synthesis PTH, 630 fails to affect FGF-23, so with PTH suppressed,
of the cell membrane calcium receptor, 76,99 (2) synthesis there is no protection against hyperphosphatemia caused
of cell membrane G proteins, and (3) function of cell by failure of renal excretion. Oral calcitriol improves sur-
membrane calcium channels. 404 Therefore, adequate vival in human renal failure patients before dialysis, 584 a
calcitriol is necessary to maintain the set-point for PTH group that corresponds to the dogs and cats with chronic
secretion. The regulation of calcium receptor expression renal failure for which veterinary use of calcitriol has been
by calcitriol explains the observed “calcium set point” recommended. 401 A large body of work now
aberrations in control of PTH secretion in those with ure- demonstrates in humans the life protection conferred
mia. 356 These patients have deficits in calcitriol produc- by calcitriol, 617,643 and in placebo-controlled studies in
tion, 116,617 as well as resistance in uremic parathyroids the dog. 456
to calcitriol 160,435 ; thus, they are less able of inducing Calcitriol is an important inhibitor of PTH synthesis,
synthesis of adequate numbers of calcium receptors. and it completes a negative feedback loop from the